Method of Risk Management for Patients Undergoing Natalizumab Treatment

ABSTRACT

Progressive multifocal leukoencephalopathy (PML) has been identified in patients taking natalizumab (NMAB) for the treatment of multiple sclerosis (MS). This patent application provides a novel method of patient screening and monitoring intended to decrease the risk of PML and other opportunistic central nervous system (CNS) diseases in patients undergoing MS therapy with NMAB, and proposes a novel method of screening and monitoring intended to decrease the risk of opportunistic disease processes of the CNS during the treatment of other medical disorders with NMAB.

This application is divided from and claims priority to U.S. patentapplication Ser. No. 11/885,615 filed Mar. 25, 2008. BACKGROUND OF THEINVENTION

Natalizumab (NMAB) is a humanized antibody that binds tosurface-expressed integrins on all leukocytes except neutrophils, andinhibits adhesion molecules on these leukocytes from binding to theircounter-receptors. In so doing, NMAB disrupts the transmigration ofthese leukocytes across endothelial tissue and into inflamed parenchymaltissue. NMAB additionally inhibits recruitment and inflammatory activityof activated immune cells. Although the exact mechanism of action ofNMAB is unclear, it is thought that at least part of the therapeuticbenefit of NMAB in the treatment of MS is due to NMAB's ability todecrease the number of activated inflammatory cells, includingT-lymphocytes, across the blood-brain barrier (BBB), thus decreasing thedegree of inflammation within the CNS.

MS is considered to be a chronic inflammatory disease of the CNS, whichis often due to myelin sheath and axonal CNS damage secondary to anautoimmune inflammatory process that usually includes a T-cell response.A more virus or toxin related demyelination has also been identified asa primary disorder within oligodendrocytes. In double blind,multi-center, placebo controlled trials, a therapeutic benefit of NMABhas been observed in patients with MS; and this is, at least in part,attributed to decreasing the extent of T-lymphocyte entry across the BBBand into the CNS, and therefore decreasing pathologic inflammatorydisease within the CNS.

Unfortunately, in 2005 it was observed that three patients who had beentreated with NMAB were diagnosed with Progressive Multi-focalLeukoencephalopathy (PML), a rare and often fatal disease of the brainthat has been observed historically in immunosuppressed patients. Whileit is not definitively clear at the time of this application whether ornot the diagnosed PML was caused by treatment with NMAB or simplyassociated with same, the inventors' understanding of the etiology ofPML leads them to believe that the former is more likely. PML isprogressive (over time it continues to encroach more and more braintissue), multi-focal (occurs in more than one location within thebrain), and is a disease of the white matter of the brain(leukoencephalopathy). Like MS, PML causes demyelination and can resultin severe and often fatal neurological injury. The etiology of PML isunderstood to originate from a virus, the JC Virus, which can infect andkill oligodendrocytes, which are specialized neural cells that producethe myelin essential for proper neuronal function.

While still rare, the resurgence of PML during the past two decades wasin part due to the compromised T-cell mediated immunity associated withpatients with AIDS. In short, treatment with NMAB results in a CNSimmunosuppression of sorts, akin (at least form the point of view of theCNS) to the more ubiquitous T-cell immunosuppression observed inpatients with AIDS. It has also been observed that there is anassociation between JC Virus-specific cytotoxic T lymphocytes (CTL) andthe early control of PML. That is, the more JC Virus-specific CTL, themore favorable outcome in patients with PML.

Although far from universal, prolonged PML survival after Highly ActiveAntiretroviral Therapy (HAART) (against the AIDS virus) has beenreported and prolonged survival has been observed with JC Viralclearance from the CSF.

DESCRIPTION OF THE INVENTION

The invention relates in part to an appreciation that should PML oranother opportunistic CNS disease occur as a result of CNSimmunosuppression secondary to NMAB therapy, then the sooner NMABtherapy is discontinued, the more likely a patient will minimize CNSdamage due to a CNS opportunistic disease, and the more likely that thatsame patient will recover. Because MS can be such a devastating disease,because treatment options for MS (and other medical disorders that maypotentially benefit from NMAB therapy) are relatively limited, becauseNMAB has shown significant clinical benefit to MS patients in properclinical studies, and because all medications carry risk and areassessed by their risk to benefit ratio, it may not be necessary topermanently remove NMAB as a therapeutic option for patients. Rather, itmay be possible to create a means of managing the risk associated withNMAB, and in particular to produce a method of screening and monitoringpatients undergoing NMAB therapy to minimize the risk of opportunisticCNS disease that may occur secondary to CNS immunosuppression.

The invention provides methods to address not only the risk of PML inpatients treated with NMAB, but to also address other opportunisticdiseases of the CNS that may result from a compromised CNS T-cell immuneresponse due to treatment with NMAB. Diseases of the CNS that may occuras a result of CNS T-cell mediated immunosuppression include but are notlimited to PML (secondary to the JC Virus), cytomegalovirus (CMV)infection, toxoplasmosis, cryptococcosis, tuberculosis (TB) and primaryCNS lymphoma (PCL) which is almost always due to Epstein-Barr Virus(EBV).

PREFERRED MODES OF PRACTICING THE INVENTION Prior To Beginning TreatmentWith NMAB A Baseline Screening Evaluation Should Be Undertaken

Prior to beginning treatment with NMAB and prior to CSF assessment, apatient should first be required to have an MRI brain imaging study,which will also serve as a baseline study with which to compare futureMRI brain images.

Prior to the initiation of NMAB therapy, cerebrospinal fluid (CSF) fromthe intended patient should be tested by polymerase chain reaction (PCR)(or other diagnostic assay if it is more sensitive) to detect thepresence of one or more of CMV, JC Virus, Toxoplasma gondii, EBV,Cryptococcus neoformans, and TB.

Prior to beginning treatment with NMAB, a patient should also berequired to have an ophthalmologic examination to establish and documenta baseline retinal status and to rule out the presence of ocular CMV(the optic nerve is a component of the CNS and may be observed in partby a simple ocular examination).

The presence of a positive CSF PCR (or other more specific diagnostictest) for CMV, EBV, TB, JC Virus, Toxoplasma gondii, or Cryptococcusneoformans; or a diagnosis of CMV retinitis on ophthalmologicexamination, should immediately disqualify a patient from treatment withNMAB.

Interval Monitoring In A Patient Undergoing Treatment With NMAB

Because it is not clear whether PML is due to an infection with a latentJC Virus, or a JC Virus acquired by exposure after CNS immunosuppressiondue to NMAB or AIDS, and because likewise is the case for CMV, TB, EBV,Toxoplasma gondii, and Cryptococcus neoformans; it will be desirable toperform interval evaluations (and if necessary, interventions) ofpatients undergoing treatment with NMAB to reduce the risk ofopportunistic disease resulting from CNS immunosuppression.

Interval Monitoring for patients undergoing NMAB treatment can bedivided into two categories:

1) No Clinical Disease Progression: In this instance, a patient'shistory and physical exam demonstrate no progression of a patient's MSor other medical disorder, and no signs or symptoms of a potentialopportunistic infection. As such, the Baseline Screening Evaluationshould be performed on an annual basis and the patient's MS or othermedical disorder should be treated according to standard treatmentguidelines for the particular medical disorder. In this case, IntervalMonitoring takes place on a regular annual basis.

2) Clinical Disease Progression: In this instance, when a patient'shistory and/or physical exam indicate a progression of the underlyingmedical disorder such as MS, or symptoms and/or signs of a potentialopportunistic disease process; an additional screening process (theProgression Screening Process) is undertaken immediately uponidentifying the progression to rule out a CNS opportunistic diseaseprocess. This screening process incorporates the same group of studiesindicated for the Baseline Screening Evaluation. Again, it is importantto perform the MRI brain imaging studies prior to performing CSF studiesas toxoplasmosis can create a mass effect that might make a lumbarpuncture contraindicated. While the inventors are not aware of anidentified case of toxoplasmosis in a patient undergoing NMAB treatment,toxoplasmosis is a well-known and treatable opportunistic infection ofthe CNS in immunocompromised patients. Should greater numbers ofpatients undertake NMAB therapy, this opportunistic infection may arise.Thus, this precaution of prioritizing brain MRI evaluation before CSFexamination is reasonable.

If MRI, CSF, or ophthalmologic examination of the Progression ScreeningProcess uncovers an opportunistic CNS disease process, then NMAB therapyshould be immediately discontinued and proper assessment and treatmentof the identified opportunistic disease process should be undertaken.

If MRI, CSF, and ophthalmologic examination of the Progression ScreeningProcess uncover no opportunistic disease, then a patient may continueNMAB therapy. In this case, within two weeks of the ProgressionScreening Process, a second lumbar puncture is performed to evaluate theCSF a second time (the Post-Progression Second Screen). Once again, theCSF is tested by PCR (or by another more sensitive assay if it isavailable) for one or more of CMV, JC Virus, EBV, TB, Toxoplasmosis, andCryptococcus. The reason for the Post-Progression Second (CSF) Screenwithin two weeks of the Progression (CSF) Screen is the result of theimperfect sensitivity of PCR analysis. As examples, one diagnostic CSFPCR study for the JC Virus was 76% sensitive; another was 92% sensitive.Once a diagnostic study has a sensitivity of 99%, that particular CSFstudy can be eliminated from the Post-Progression Second (CSF) Screen.

If both the Progression Screening Process and the Post-ProgressionSecond Screen provide no indication of an opportunistic disease processwithin the CNS, then the ongoing treatment of the patient with MS (orother medical disorder) continues according to standard treatmentguidelines for the particular medical disorder.

Subsequently, if a patient's history and physical exam then indicate noprogression of the underlying medical disorder such as MS, nor symptomsnor signs of a potential opportunistic disease process, then a BaselineScreening Evaluation should be repeated one year after the last negativePost-Progression Second Screen.

However, if subsequently a patient's history and/or physical examindicate a positive progression of the underlying medical disorder suchas MS, and/or signs or symptoms of a potential opportunistic CNS diseaseprocess, then the time for the next Progression Screening Process shouldbe at a minimum of two to three months following the last negativePost-Progression Second Screen.

This Interval Monitoring continues for as long as a patient is treatedwith NMAB.

To emphasize, the proposed method of screening and monitoring patientsundergoing NMAB treatment for MS and other medical disorders, isintended to minimize, but will not eliminate, the risk of opportunisticCNS disease that may occur as a result of impaired CNS T-cell immunitydue to NMAB therapy.

1. A method of reducing risk associated with administration ofnatalizumab to a patient comprising: before initiating natalizumabtreatment, obtaining an MRI image of the patient's brain establishing abaseline MRI image; initiating natalizumab treatment in the absence ofevidence of potential opportunistic disease from the MRI image; after apredetermined time and before administering a subsequent natalizumabdosage, obtaining a subsequent MRI image of the patient's brain andcomparing the subsequent MRI image with the previous MRI image;continuing natalizumab treatment in the absence of evidence of potentialopportunistic disease in the subsequent MRI image, or withholdingnatalizumab treatment if evidence of potential opportunistic disease isdetected in the subsequent MRI image.
 2. The method of claim 1 furthercomprising: if evidence of potential opportunistic disease is detectedin the MRI image, obtaining a sample of the patient's cerebrospinalfluid (CSF); testing the sample for the presence of a precursor of theopportunistic disease; and continuing natalizumab treatment if there isno indication of the precursor in the sample.
 3. The method of claim 1wherein the recited steps are repeated at regular, periodic intervalsduring the course of natalizumab treatment.
 4. The method of claim 2wherein the recited steps are repeated at regular, periodic intervalsduring the course of natalizumab treatment.
 5. The method of claim 1wherein the natalizumab treatment is continued and further comprisingthe steps of: obtaining an MRI image at any time during the course ofnatalizumab treatment upon the appearance of signs or symptoms of apotential opportunistic disease; examining the MRI image for evidence ofthe potential opportunistic disease; and withholding natalizumabtreatment if evidence of the potential opportunistic disease is detectedin the MRI image; or continuing natalizumab treatment in the absence ofevidence of the potential opportunistic disease from the MRI image. 6.The method of claim 5 further comprising: if evidence of a potentialopportunistic disease is detected in the MRI image, obtaining a sampleof the patient's cerebrospinal fluid (CSF); testing the sample for thepresence of a precursor of the opportunistic disease; and continuingnatalizumab treatment if there is no indication of the presence of theprecursor in the sample.
 7. The method of claim 1 wherein the steps ofobtaining a subsequent MRI image and comparing the image with theprevious image are performed before administration of each dosage ofnatalizumab.
 8. A method of reducing a risk associated withadministration of natalizumab to a patient undergoing such treatmentcomprising: screening the patient for potential progressive multifocalleukoencephalopathy (PML) by obtaining and examining an MRI image of thebrain, determining the presence of evidence of potential PML byreference to the MRI image; withholding natalizumab treatment if thepresence of evidence of potential PML is detected; or continuingnatalizumab treatment in the absence of evidence of potential PML. 9.The method of claim 8 comprising the further steps of obtaining andexamining an MRI image for the presence of evidence of potential PML atregular, periodic intervals during the course of natalizumab treatment;and withholding natalizumab treatment if the presence of evidence ofpotential PML is detected; or continuing natalizumab treatment in theabsence of evidence of potential PML.
 10. The method of claim 8 whereinnatalizumab treatment is continued and further comprising the steps of:obtaining an MRI image at any time during the course of natalizumabtreatment upon the appearance of signs or symptoms of potential PML; andwithholding natalizumab treatment if evidence of potential PML isdetected in the MRI image; or continuing natalizumab treatment in theabsence of evidence of potential PML from the MRI image.
 11. The methodof claim 8 wherein the steps of obtaining a subsequent MRI image andcomparing the image with the previous image are performed beforeadministration of each dosage of natalizumab.
 12. A method of reducingrisk associated with administration of natalizumab to a patientcomprising: obtaining an MRI image of the patient's brain establishing abaseline MRI image; after a predetermined time and before administeringa subsequent natalizumab dosage, obtaining a subsequent MRI image of thepatient's brain and comparing the subsequent image with the previousimage; continuing natalizumab treatment in the absence of evidence ofpotential opportunistic disease in the subsequent image, or if evidenceof potential opportunistic disease is detected in the MRI image,obtaining a sample of the patient's cerebrospinal fluid (CSF); testingthe CSF sample for the presence of a precursor of the opportunisticdisease; and withholding natalizumab treatment if the precursor ispresent in the CSF sample or continuing natalizumab treatment if theprecursor is not present in the CSF sample.
 13. The method of claim 12wherein the steps of obtaining a subsequent MRI image and comparing theimage with the previous image are performed before administration ofeach dosage of natalizumab.
 14. The method of claim 13 wherein theopportunistic disease comprises PML and the precursor comprises JCvirus.
 15. The method of claim 12 wherein the opportunistic diseasecomprises PML and the precursor comprises JC virus.
 16. The method ofclaim 12 wherein the recited steps are repeated at regular, periodicintervals during the course of natalizumab treatment.
 17. The method ofclaim 16 wherein the opportunistic disease comprises PML and theprecursor comprises JC virus.
 18. The method of claim 12 wherein thenatalizumab treatment is continued and further comprising the step ofobtaining the MRI at any time during the course of natalizumab treatmentupon the appearance of signs or symptoms of a potential opportunisticdisease.
 19. The method of claim 18 wherein the opportunistic diseasecomprises PML and the precursor comprises JC virus.